1. Technical Field of the Invention
The subject matter of this patent is the diagnostic use of selective adenosine receptor agonists as artificial or pharmacologic stressors to assess myocardial perfusion and function.
2. Prior Art
Persons having or whom are suspected of having coronary artery disease are often referred for diagnostic tests known as myocardial perfusion imaging procedures. This family of procedures comprises powerful diagnostic tools for determining both the presence and extent of coronary artery disease. The rationale behind these procedures is that certain cardiac abnormalities may not manifest themselves at rest (i.e., the patient is in the normal or unexerted state), though their presence will become apparent if oxygen demand is increased so that the blood flow through the heart increases (for instance, during vigorous exercise). Thus, though an arterial occlusion may be too small to affect blood flow through the heart at rest-when flow rate is low-the presence of the occlusion is much more likely to become apparent if blood flow is increased. Therefore, myocardial function is often assessed while the patient is under stress, or conditions of increased blood flow through the major vessels.
One very common means of inducing stress is to have the patient walk on a treadmill. Once the desired blood flow levels are achieved through the suspected occluded regions, blood flow through this region(s) is monitored. One means by which this monitoring can occur is by injecting the patient with a compound known as a tracer, such as thallium-201. This is a radioactive compound, thus, its presence is observable by typical radiation-detection devices positioned near the patient. Since the tracer is quickly removed from the bloodstream, and absorbed by the heart muscle cells, and since the concentration of the tracer at a given location in the heart muscle is proportional to the amount of blood flowing through the vessel, it is, therefore possible--by observing the amount of tracer into the heart muscle--to indirectly monitor the blood through the vessel of interest. Low levels of blood flow--as evidenced by low tracer levels--at a certain point in the vessel may indicate an occlusion.
Yet many patients with suspected or documented coronary artery disease are unable to exercise, thus it is desirable to induce myocardial stress (to increase blood flow through the heart) by an "artificial" means. This is the function of pharmacological stressors, such as those disclosed in the method of the present Invention. These chemical compounds, upon administration to a patient, mimic the effects of exercise, thus they allow the physician to detect the presence of myocardial occlusions, as blood flow through the suspected occluded region is transferred.
At the present time, two pharmacological stress agents are approved by the FDA, for use as adjuncts to myocardial perfusion imaging. These are adenosine and dipyridamole. Additionally, in a 1993 review article, one investigator listed several viable candidates: adenosine, dipyridamole, and dobutamine. Verani, M. S., Pharmacologic Stress Myocardial Perfusion Imaging, 28 Cur. Probs. in Cardiol. 481 (1993). Additional perfusion imaging agents have also been the subject of patent applications. U.S. Pat. No. 5,477,857, by McAfee et al. and assigned to Discovery Therapeutics, Inc., discloses methods for diagnosing myocardial dysfunction based on hydrazinoadenosine-based compounds. Similarly, U.S. Pat. No. 5,070,877, by Mohiuddin and Hillerman, and assigned to MeDco Research, Inc. discloses the use of adenosine as a myocardial perfusion agent to detect coronary disease.
Adenosine is the current state-of-the-art pharmacological stressor for use in myocardial imaging. The efficacy of adenosine in diagnosing coronary artery disease has been well-studied. Verani, M. S., Mahmarian, J. J., Hixson, J. B., Boyce, T. M., Staudacher, R. A., Diagnosis of Coronary Artery Disease by Controlled Coronary Vasodilation With Adenosine and Thallium-201 Scintigraphy in Patients Unable to Exercise, 82 Circulation 80 (1990); Mahmarian, J. J., Mahmarian, A. C., Marks, G. F., Pratt, C. M., Verani, M. S., Role of Adenosine Thallium-201 Tomography for Defining Long-Term Risk in Patients After Acute Myocardial Infarction, 25 JACC 1333 (1995). In addition, its safety, quite naturally, has been the subject of intensive study. Korkmaz, M. E., Mahmarian, J. J., Guidry, G. W., Verani, M. S., Safety of Single-Site Adenosine Thallium-201 Scintigraphy, 73 Amer. J. of Cardiol. 200 (1994). Finally, although other candidates, such as those disclosed above, have been suggested as possible replacements for adenosine, no successful replacement has yet been found, despite the promising experimental data based on these compounds. This fact illustrates the highly unpredictable nature of compounds of this type when used for this particular purpose. Indeed, while efficacy may, in certain instances, be easier to predict, the broad spectrum of potential (and potentially life-threatening) side effects is far, far more difficult to predict.
The pharmacological activity of both adenosine and dipyridamole, as it relates to myocardial perfusion imaging, results from stimulation of the adenosine A.sub.2A receptors. Yet these two compounds are nonselective for this receptor, and also bind to the A.sub.1 and A.sub.3 adenosine receptors. According to the current orthodoxy, this nonselective binding--or binding to receptors other than the target receptor--is largely responsible for the numerous side effects that these two compounds exhibit. The uncertainty of this statement should not be dismissed; in other words, a compound that binds more selectively to the A.sub.2A receptor is not necessarily a superior candidate for a pharmacological. Indeed, as in nearly all facets of biomedical research, the actual results are quite unpredictable.
Again, nonspecific binding, or binding to other than the A.sub.2A receptor is thought to be responsible for many of the undesirable side effects of pharmacological stressors, most notably adenosine. Some of these side effects are potentially serious, including advanced-degree atrioventricular block. Verani, M. Adenosine Stress Imaging, 3 Coronary Artery Disease 1145, 1147 (1992).
Therefore, a compound that exhibits, among other things, high selectivity towards the A.sub.2A receptor is highly desirable for further investigation as a possible candidate for an improved pharmacological stressor. The family of compounds disclosed in this Application are based on 2-p-(2-Carboxymethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine hydrochloride, known commercially as CGS-21680. The compounds known as CGS-21680 has been previously disclosed. In addition, the greater selectivity of CGS-21680 over adenosine for the A.sub.2A receptor (i.e., greater binding to the A.sub.2A receptor and less to the A.sub.1 receptor). According to one study from the prior art, CGS-21680 exhibits a 170-fold selectivity for A.sub.2A over the A.sub.1 receptor. Jarvis, M. F., Schulz, R. Hutchinson, A. J., Do, U. H., Sills, M. A., Williams, H. [.sup.3 H]CGS 21680, a selective A.sub.2 receptor agonist directly labels A.sub.2 receptors in rat brain. 251 J. Pharmacol. Exp. Ther. 888 (1989). In addition, the potent vasodilator effect of CGS-21680 has likewise been previously disclosed. Yet its use as a pharmacologic stressor has not previously been disclosed nor suggested. Though the link between a compound's vasodilatory activity and its efficacy as a pharmacologic stressor is highly unpredictable, the present Invention discloses the use of CGS-21680 and related compounds for use as pharmacologic stressors.